DESCRIPTION (taken from application) The colon crypt-to-lumen axis is a paradigm of orderly cellular proliferation, differentiation and senescence. The initial genomic response to mitogenic growth factors parallels that of other dividing cells, with expression of the immediate-early response genes. One of these genes, Nup475, is the prototype of a new family of nuclear regulatory proteins that contain Cys3His motifs. Expressed in response to wide range of growth factors and cytokines, Nup475 has recently been implicated as a potent regulator of the cellular response to TNF-a. The focus of this proposal is to characterize the role of Nup475 in: 1. The effects of Nup475 over-expression on the phenotype of colonocyte-like cells. 2. Changes in nuclear transcription factors responsible for growth and cytokine-related phenomena by Nup475 expression. 3. Modulation of cytokines and other genes by Nup475 expression in response to TNF-a stimulation. This proposal is designed to provide molecular and cellular biology experience to the Principal Investigator using the resources of the University of Virginia Gastroenterology and Microbiology Research laboratories, the strengths of two sponsors in immunology and epithelial cell biology, and a rigorous program of laboratory and classroom instruction. This is in keeping with the investigator's goal of obtaining cell biology experience as part of a career focusing on molecular aspects of carcinogenesis.